Intraocular inoculation of mice with HSV leads to an infection of the ipsilateral superior cerival ganglion (SCG) of the autonomic nervous system that can be divided into 2 phases: 1) an acute lytic phase lasting approximately one week during which infectious virus in high titer is demonstrable in homogenates of the ganglia, and 2) a prolonged latent phase during which homogenates are invariably negative for virus although the continued presence of HSV is detected using explanation and cocultivation techniques. In these animals, virus reaches the SCG after intraocular inoculation principally over neural pathways, although intravenous injection of virus can also produce a latent SCG infection. When mice and pre-immunized either with passively administered antibody or with live HSV given intraperitoneally shortly before intraocular challenge, viral titers in the acute phase of infection are markedly reduced, but the prevalence of latent infection is actually enhanced. Latent virus can be reactivated in these animals by ipsilateral postganglionic neurectomy: on the 4th day after neurectomy, homogenates of ganglia in 9% of mice yield infectious virus while control animals remain negative. Treatment of mice with cyclophosphamide at the time of neurectomy increases the number of mice with homogenate-postive ganglia to 40% and prolongs the period during which infectious virus can be recovered. Administration of antithymocyte serum (ATS) before neurectomy also prolongs the period of viral recovery although the incidence of reactivation in these mice is not increased. Neither cyclophosphamide nor ATS reactivate virus in the absence of neurectomy. These results suggest that postganglionic neurectomy induces an intrinsic alteration in the permissiveness of ganglion cells for HSV, and that elimination of the reactivated virus involves immune defenses that are, in part, independent of T-lymphocyte activity.